Ehlers-Danlos Syndrome Type IV

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: COL3A1 (HGNC:2201)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 07/01/2014
• Curation Status: Released - Under Revision (1.2.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
COL3A1	N/A ()	130050	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Vascular or organ rupture or perforation / Avoidance of invasive procedures	3	3C	2A	2	10CA

Severity of Outcome

Prevalence of the Genetic Condition

There are no good current estimates of the prevalence of Ehlers-Danlos Syndrome (EDS) type IV in any population because a large proportion of cases remain undiagnosed. A minimum prevalence of about 1:200,000 can be estimated by extrapolating from the number of known individuals with genetic testing, biochemical, or pedigree-confirmed diagnoses in the United States.EDS type IV appears to constitute approximately 5-10% of all EDS cases.

Clinical Features (Signs / symptoms)

EDS type IV, or vascular EDS, is characterized by thin, translucent skin; easy bruising; characteristic facial appearance (in some individuals); and arterial, intestinal, and/or uterine fragility. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in the majority of adults identified to have EDS type IV. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously.The vascular complications may affect all anatomical areas; spontaneous rupture of the aorta and medium-to-large size vessels are the most frequent complications reported. There is also a high risk of recurrent perforation in the sigmoid colon.

Natural History (Important subgroups & survival / recovery)

The overall mortality of EDS type IV is 90% by the age of 50 because of spontaneous rupture of vessels and internal organs.The median survival for individuals with EDS type IV is 48 years.Vascular fragility is dominant in the third and fourth decade.Pregnancy increases the likelihood of a uterine or vascular rupture. Pregnancy for women with EDS type IV confers as much as a 12% risk for death from peripartum arterial rupture or uterine rupture.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

< 1-2 in 100000

The prevalence of individuals with mutations in COL3A1 is estimated to range from 1:50,000 to 1:200,000.

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Penetrance appears to be close to 100% with missense or exon-skipping mutations; the age at which the mutation becomes penetrant may vary

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

NA

Expressivity

There is high variability in disease expression, highlighted by the fact that clinical diagnosis is based on any two of four possible major diagnostic criteria, and that two or more of thirteen possible minor diagnostic criteria are supportive but not sufficient for diagnosis.

Tier 4

A subpopulation of individuals with EDS type IV (3-4%) have haploinsufficiency mutations; improved outcomes are reported in this group, including a 15-year delay in onset of complications, similarly improved life expectancy, and paucity of both obstetric and bowel complications.

Tier 4

Intervention Effectiveness

Patient Management

Information on the effectiveness of the patient management recommendation(s) below was not provided.Currently, no consensus exists regarding the appropriate extent of evaluation at the time of initial diagnosis. Approach to a vascular evaluation depends on the age of the individual and the circumstances in which the diagnosis is made.

Tier 4

Invasive procedures (treatment, diagnostic, etc.) should be avoided, except in life-threatening situations.

Tier 1

Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain.

Tier 4

Educating pregnant women with EDS type IV as to possible complications, and frequent surveillance in a high-risk obstetrical program is recommended. Pregnancy for women with EDS type IV has as much as a 12% risk for death from peripartum arterial or uterine rupture.

Tier 4

A MedicAlert bracelet should be worn.

Tier 4

Surveillance

There are no published data that assess the efficacy of screening strategies to identify the regions in the arterial vasculature at highest risk.

Circumstances to Avoid

Individuals with EDS type IV should not engage in any competitive athletic activity.

Tier 2

Unless the procedure is considered absolutely life-saving, surgery and all other invasive procedures should be avoided whenever possible.

Tier 1

Examples of invasive procedures: - Diagnostic colonoscopy should not be performed in patients with EDS type IV.

Tier 1

- Arteriograms are not recommended.

Tier 3

Nature of Intervention

Nature of Intervention

Management could result in significant alterations to lifestyle choices (pregnancy, participation in sports) and medical treatment/screening

Context: Adult

Chance to Escape Clinical Detection

Because many families with EDS type IV are identified only after a severe complication or death, it is likely that individuals/families with COL3A1 mutations with a mild phenotype do not come to medical attention and, therefore, go undetected

Context: Adult

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			COL3A1			130050

References List

Bergqvist D, Bjorck M, Wanhainen A. (2013) Treatment of vascular Ehlers-Danlos syndrome: a systematic review. Annals of surgery. 258(2):257-61.

Burcharth J, Rosenberg J. (2012) Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: a systematic review. Digestive surgery. 29(4):349-57.

EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANT. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 130050, (2016) World Wide Web URL: http://omim.org/

Ehlers-Danlos syndrome, vascular type. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=286

Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. (2010) 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. Journal of the American College of Cardiology. 55(14):e27-e129.

Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. (2005) Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. Journal of the American College of Cardiology. 45(8):1340-5.

MG Pepin, ML Murray, PH Byers. Vascular Ehlers-Danlos Syndrome. (1999) [Updated Nov 19 2015]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1494/